An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer

Phase 2

Completed

Conditions: Prostate Cancer
Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Interventions: Drug: AZD4635
Drug: Durvalumab
Drug: Oleclumab

Registration Number: NCT04089553

Lead Sponsor: AstraZeneca

Brief Summary: This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arms (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

Detailed Description: This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arm (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

All participants will be allocated into a module using an Interactive Web Response System (IWRS). Randomization will occur when patients meet eligibility criteria for two or more modules that are currently recruiting. If participants only meet the criteria for one currently recruiting module, they will be allocated to that module without randomization taking place.

The primary objective of the clinical study is to evaluate the efficacy of each combination therapy by: 1) assessing the objective response rate (ORR) of participants with measurable disease (response will be determined by Response Evaluation Criteria in Solid Tumours \[RECIST 1.1\]); 2) assessing the prostate-specific antiget (PSA) confirmed response rate of each combination therapy (PSA confirmed response rate is defined as the proportion of participants with a reduction in the PSA level of ≥50% measured from baseline to the lowest post-baseline PSA result measured twice, at least 3 weeks apart by the Prostate Cancer Working Group 3 criteria \[PCWG3\]).

The safety endpoints include assessment of adverse events and serious adverse events, physical examinations, vital signs, and collection of clinical chemistry/hematology parameters

There will be approximately 30 PSA evaluable participants in each module, and approximately 20 participants will have RECIST measurable disease at baseline in each module. If any of the required participants for PSA and/or ORR are not evaluable for PSA response or tumor response, respectively, they may be replaced at the sponsor's discretion.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 59

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Module 1 (AZD4635 75 mg + Durvalumab 1500 mg)	AZD4635	Participants will receive monotherapy of AZD4635 75 mg orally once daily (QD) for first 14 days and thereafter will continue to receive 75 mg orally QD in combination with durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) until will derive clinical benefit as judged by the investigator, confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.
Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg)	AZD4635	Participants will receive combination therapy of AZD4635 (50 mg / 75 mg orally QD) and oleclumab 1500 mg IV (every 2 weeks of 28-day cycle for the first 4 doses and Q4W thereafter) until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.
Module 1 (AZD4635 75 mg + Durvalumab 1500 mg)	Durvalumab	Participants will receive monotherapy of AZD4635 75 mg orally once daily (QD) for first 14 days and thereafter will continue to receive 75 mg orally QD in combination with durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) until will derive clinical benefit as judged by the investigator, confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.
Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg)	Oleclumab	Participants will receive combination therapy of AZD4635 (50 mg / 75 mg orally QD) and oleclumab 1500 mg IV (every 2 weeks of 28-day cycle for the first 4 doses and Q4W thereafter) until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Confirmed Objective Response Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)	The confirmed objective response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines, assessed by computed tomography (CT) scan/ magnetic resonance imaging (MRI) scan/ positron emission tomography (PET) scan and bone scan. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.
Percentage of Participants With Confirmed Prostate-specific Antigen (PSA) Response Per Prostate Cancer Working Group 3 (PCWG3) Criteria	Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)	A confirmed PSA response is defined as reduction in the PSA level of \>= 50% from baseline to the lowest post-baseline PSA results, measured twice, at least 3 weeks apart by the PCWG3 criteria.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Radiological Progression Free Survival (rPFS) at 6 Months	Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)	The rPFS is defined as the time interval from the first dose of AZD4635 until the date of radiological disease progression (RECIST 1.1 for soft tissue lesions and PCWG3 criteria for bone lesions) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from study therapy or received another anti-cancer therapy prior to progression. The progressive disease for soft lesions per RECIST 1.1 (assessed by CT/MRI/PET scan) is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum in the study, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The progressive disease for bone lesions per PCWG3 is defined as at least 2 or more new metastatic bone lesions observed compared to baseline assessment (Day -28), with confirmation scan performed at least 6-week later.
Duration of Response (DoR)	Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)	The DoR is defined as the time from the date of first documented response (confirmed CR/PR) until date of documented progression or death in the absence of disease progression. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression or not evaluable response in-between. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The DoR was estimated using Kaplan-Meier method.
Overall Survival (OS)	Baseline (Day -28) through end of study (last participant last visit) (approximately 22 months)	The OS is defined as the time from date of first study dose until the date of death due to any cause. The median of OS was estimated using Kaplan-Meier method and CI was derived based on Brookmeyer-Crowley method.
Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab	Pre-dose on Day 1 of Cycles 1, 2, 4, and 7 and 90 days following the last dose of durvalumab (approximately 22 months)	The detection of the immunogenicity of monoclonal antibody to durvalumab was performed using a validated immunoassay method. Participants with positive ADA to durvalumab are reported.
Number of Participants With Positive ADA to Oleclumab	Pre-dose on Day 1 of Cycles 1, 3, 5, and every 12 weeks thereafter, and 90 days following the last dose of oleclumab (approximately 22 months)	The detection of the immunogenicity of monoclonal antibody to oleclumab was performed using a validated immunoassay method. Participants with positive ADA to oleclumab are reported.
Plasma Concentrations of AZD4635 and Its Metabolites (SSP-005173 and SSP-005174)	Predose on Day 1 of Cycle 7	Plasma concentrations of AZD4635 and its metabolites (SSP-005173 and SSP-005174) are reported.
Plasma Concentration of Durvalumab	Predose and end of infusion on Day 1 of Cycle 7	Plasma concentration of durvalumab is reported.
Plasma Concentration of Oleclumab	Predose and 10 minutes end of infusion on Day 1 of Cycle 14	Plasma concentration of oleclumab is reported.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	Day 1 through 90 days after the last dose of study drug (approximately 22 months)	An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs	Day 1 through 90 days after the last dose of study drug (approximately 22 months)	Vital signs assessment included body temperature, respiration rate, pulse rate, blood pressure, and weight. Participants with abnormal vital signs and/or abnormal physical examination reported as TEAEs are reported.
Number of Participants With Common Terminology Criteria for Adverse Events (CTCAE) Grade Change in Laboratory Parameters From Baseline to Grade 3 or More	Baseline (Day 1) through 90 days after the last dose of study drug (approximately 22 months)	Laboratory parameters included hematology, coagulation, clinical chemistry, and urinalysis. The CTCAE is a descriptive terminology is used for AE reporting. The CTCAE v5.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 as mild AE, Grade 2 as moderate AE, Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death related to AE. Participants with CTCAE v5.0 grade change in laboratory parameters from baseline (Day 1 before the start of study treatment) to Grade 3 or more are reported.